Synthesis and Characterization of Fluorine-18-Labeled N-(4-Chloro-3-((fluoromethyl-d₂)thio)phenyl)picolinamide for Imaging of mGluR4 in Brain

Abstract

We have synthesized and characterized [ 18 F]-N-(4-chloro-3-((fluoromethyl-d 2)thio)phenyl)picolinamide ([ 18 F]15) as a potential ligand for the PET imaging of mGluR4 in the brain. Radioligand [ 18 F]15 displays CNS drug-like properties, including mGluR4 affinity, potent mGluR4 PAM activity and selectivity against other mGluRs, as well as sufficient metabolic stability. Radiosynthesis was carried out in two steps. The radiochemical yield of [ 18 F]15 was 11.6 ± 2.9% (n = 7, decay corrected) with a purity of 99% and a molar activity of 84.1 ± 11.8 GBq/ μmol. Ex vivo biodistribution studies showed reversible binding of [ 18 F]15 in all investigated tissues including the brain, liver, heart, lungs, and kidneys. PET imaging studies in male Sprague-Dawley rats showed that [ 18 F]15 accumulates in the brain regions known to express mGluR4. Pretreatment with the unlabeled mGluR4 PAM compounds 13 (methylthio analog) and 15 showed significant dose-dependent blocking effects. These results suggest that [ 18 F]15 is a promising radioligand for PET imaging mGluR4 in the brain.

Detailed radiosynthesis of [18F]mG4P027 as a positron emission tomography radiotracer for mGluR4

“…The fraction containing purified [ 18 F] 2 was diluted with water (10 times the fraction volume, around 40 ml) in order to trap [ 18 F] 2 on a C18 Sep‐Pak column. The C18 Sep‐Pak column was then dried under a flow of nitrogen gas for 20–30 min, 17 which was then washed off the C18 Sep‐Pak column by 0.7 ml of dry DMSO to a reaction vessel for the next step. Because a large amount of water had been brought into the column (40 ml), this drying step was tedious, time‐consuming and difficult to control the water content in the eluting DMSO solution, which might create significant problems for the following step.…”

“…[ 18 F]‐ N ‐(4‐chloro‐3‐((fluoromethyl‐ d 2 )thio)phenyl)‐picolinamide ([ 18 F] mG4P027 ) as a potential radiotracer for PET imaging of mGluR4 in the brain was designed and characterized 17 . Now, we are interested in further developing its labeling strategy for a few reasons.…”

“…[ 18 F]-N-(4-chloro-3-((fluoromethyl-d 2 )thio)phenyl)picolinamide ([ 18 F]mG4P027) as a potential radiotracer for PET imaging of mGluR4 in the brain was designed and characterized. 17 Now, we are interested in further developing its labeling strategy for a few reasons. Firstly, 18 F is often the radionuclide of choice for both its physical and nuclear characteristics and its half-life is sufficient to carry out relatively extensive imaging protocols when compared with what is impossible with 11 C ([ 11 C]PXT012253).…”

A case study of foliglurax, the first clinical mGluR4 PAM for symptomatic treatment of Parkinson’s disease: translational gaps or a failing industry innovation model?

“…As a comparison, another advanced mGluR4 PAM compound, valiglurax (15) was reported to enhance the E MAX of glutamate in in vitro tests up to 300% of glutamate E MAX [78,79]. Lundbeck and Prexton used a newly developed PET tracer ([11C]-PXT012253), studied it in rat and nonhuman primate [76,94], and conducted a clinical study (NCT04175132) to understand and characterize the degree of receptor occupancy at the PAM site that is associated with therapeutic occupancy in nonclinical species. The preclinical work has been published [76,94].…”

“…Lundbeck and Prexton used a newly developed PET tracer ([11C]-PXT012253), studied it in rat and nonhuman primate [76,94], and conducted a clinical study (NCT04175132) to understand and characterize the degree of receptor occupancy at the PAM site that is associated with therapeutic occupancy in nonclinical species. The preclinical work has been published [76,94]. This is admirable, as companies rarely publish all supporting evidence prior to the conduct of clinical POC studies, to avoid enabling competitors.…”